Back to EveryPatent.com
United States Patent |
5,073,641
|
Bundgaard
,   et al.
|
December 17, 1991
|
Prodrug derivatives of carboxylic acid drugs
Abstract
Novel ester derivatives of carboxylic acid medicaments of formula (I),
wherein R--COO--represents the acyloxy residue of a carboxylic acid drug
or medicament, n is an integrer from 1 to 3, and R.sub.1 and R.sub.2 are
the same or different and are selected from a group consisting of an
alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may
be unsubstituted or substituted, or R.sub.1 and R.sub.2 together with the
N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to
the nitrogen atom may contain one or two further heteroatoms selected from
the group consisting of nitrogen, oxygen and sulfur and which heterocyclic
group may be substituted. These compounds are highly biolabile prodrug
forms of the corresponding carboxylic acid compounds and are highly
susceptible to undergoing enzymatic hydrolysis in vivo whereas they are
highly stable in aqueous solution. The novel derivatives are less
irritating to mucosa than the parent carboxylic acids and may provide an
improved bio-availability of the drugs.
Inventors:
|
Bundgaard; Hans (Tjornevej 36, DK-2970 Horsholm, DK);
Nielsen; Niels M. (Cumberlandsgade 15, st.th., DK-2300 Copenhagen, DK)
|
Appl. No.:
|
188407 |
Filed:
|
April 26, 1988 |
PCT Filed:
|
August 25, 1987
|
PCT NO:
|
PCT/DK87/00104
|
371 Date:
|
April 26, 1988
|
102(e) Date:
|
April 26, 1988
|
PCT PUB.NO.:
|
WO88/01615 |
PCT PUB. Date:
|
March 10, 1988 |
Foreign Application Priority Data
Current U.S. Class: |
560/56; 548/500; 549/494; 560/39; 560/49; 560/105; 560/153 |
Intern'l Class: |
C07C 069/76 |
Field of Search: |
560/56,39,49,105,153
548/500
549/494
|
References Cited
Foreign Patent Documents |
0106541 | Apr., 1984 | EP.
| |
0224178 | Jun., 1987 | EP.
| |
0227355 | Jul., 1987 | EP.
| |
0237051 | Sep., 1987 | EP.
| |
86/00066 | Jan., 1986 | WO.
| |
Other References
CA vol. 106 #78187t, Mar. 16, 1987.
Ehrhart, G. et al., Arzneimittel 1972, 2, 432.
|
Primary Examiner: Killos; Paul J.
Attorney, Agent or Firm: Birch, Stewart, Kolasch & Birch
Claims
We claim:
1. Compounds of the formula I
##STR38##
wherein R--COO-- represents the acyloxy residue of a carboxylic acid drug
or medicament selected from:
Indomethacin
Naproxen
Ibuprofen
Flurbiprofen
5-Aminosalicylic Acid
L-Dopa
Furosemide and
N-Acetylcysteine
and R.sub.1 and R.sub.2 are the same or different and are selected from a
group consisting of an alkyl group, an alkenyl group, an aryl group, an
aralkyl group, a cycloalkyl group, in which the alkyl, alkenyl, aryl,
aralkyl or cycloalkyl group is unsubstituted or substituted with one or
more substituents selected from:
a halogen atom,
a hydroxy group,
a straight or branched-chain alkoxy group having the formula R.sub.3 --O--,
wherein R.sub.3 represents an alkyl group or an aryl group, which groups
may be unsubstituted or substituted with one or more of a halogen atom or
a hydroxy group,
a carbamoyl group having the formula
##STR39##
wherein R.sub.4 and R.sub.5 are the same or different and are hydrogen, an
alkyl group or are selected from a group having the formula --CH.sub.2
NR.sub.7 R.sub.6, wherein R.sub.6 and R.sub.7 are the same or different
and are hydrogen, or an alkyl group,
an amino group having the formula --NR.sub.8 R.sub.9, wherein R.sub.8 and
R.sub.9 are the same or different and are hydrogen, or an alkyl group
an acyloxy group having the formula --COOR.sub.10, wherein R.sub.10 is an
alkyl, aryl or aralkyl group,
an oxyacyl group having the formula R.sub.11 COO-- wherein R.sub.11 is
hydrogen, an alkyl group, an aryl group, an aralkyl group, a cycloalkyl
group, in which the alkyl, aryl, aralkyl or cycloalkyl group is
unsubstituted or substituted with one or more of a halogen atom, a hydroxy
group, an alkoxy group of the formula R.sub.3 --O-- as defined above, a
carbamoyl group of the formula --CONR.sub.4 R.sub.5 as defined above or an
amino group having the formula --NR.sub.8 R.sub.9 as defined above;
and nontoxic pharmaceutically acceptable acid addition salts thereof.
2. Compounds according to claim 1 wherein R.sub.1 is methyl or ethyl, and
KR.sub.2 is selected from
--CH.sub.3
--CH.sub.2 CH.sub.3
--CH.sub.2 CH.sub.2 OH
--CH.sub.2 CONH.sub.2
--CH.sub.2 CH.sub.2 CONH.sub.2
--CH.sub.2 CH.sub.2 OOCCH.sub.2 N(CH.sub.3).sub.2
--CH.sub.2 CH.sub.2 OOCCH.sub.2 N(C.sub.2 H.sub.5).sub.2
--CH.sub.2 CH.sub.2 OOCCH.sub.2 NH.sub.2
--CH.sub.2 CONHCH.sub.2 N(CH.sub.3).sub.2
--CH.sub.2 CONHCH.sub.2 N(C.sub.2 H.sub.5).sub.2
--CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2
--CH.sub.2 CONHCH.sub.2 NH.sub.2
--CH.sub.2 CONH--CH.sub.3.
3. Compounds of the formula I
##STR40##
wherein R.sub.1 and R.sub.2 both are alkyl or both are --CH.sub.2 CH.sub.2
OH and R--COO is the acyloxy residue of a carboxylic acid drug selected
from:
Indomethacin
Naproxen
Ibuprofen
Flurbiprofen
5-Aminosalicylic acid
L-Dopa
Furosemide and
N-Acetylcysteine.
4. Compounds according to claim 1, wherein R--COO is derived from Naproxen.
5. Compounds according to claim 3, wherein R--COO is derived from Naproxen.
6. Compounds according to claim 1, wherein R--COO is derived from L-Dopa or
N-acetylcysteine.
7. Compounds according to claim 3, wherein R--COO is derived from L-Dopa or
N-acetylcysteine.
8. A pharmaceutical composition comprising a pharmaceutically acceptable
excipient and a pharmaceutically effective amount of a compound according
to any one of claims 1-7.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel highly biolabile prodrug forms of
drugs containing one or more carboxylic acid functions, to methods for
preparing the prodrug forms, to pharmaceutical compositions containing
such prodrug forms, and to methods for using the prodrug forms.
For purposes of this specification, the term "prodrug" denotes a derivative
of a known and proven carboxylic acid functional drug (e.g. naproxen,
L-dopa, salicylic acid, etc.) which derivative, when administered to
warm-blooded animals, e.g. humans, is converted into the proven drug. The
enzymatic and/or chemical hydrolytic cleavage of the compounds of the
present invention occurs in such a manner that the proven drug form
(parent carboxylic acid drug) is released, and the moiety or moieties
split off remain nontoxic or are metabolized so that nontoxic metabolic
products are produced.
These novel prodrug forms are esters of certain hydroxy-amides. These
esters combine a high susceptibility to undergo enzymatic hydrolysis in
vivo with a high stability in aqueous solution. The new ester prodrug type
is further characterized by providing ample possibilities for varying the
aqueous solubility as well as the lipophilicity of the prodrug derivatives
with retainment of a favourable enzymatic/non-enzymatic hydrolysis index.
2. Description of the Prior Art
It is well-known that a wide variety of compounds containing carboxylic
acid functions are biologically active. For example, such structure is
characteristic of non-steroidal anti-inflammatory agents such as naproxen,
ibuprofen, indomethacin and the like; penicillin and cephalosporin
antibiotics such as ampicillin, cefmetazole and the like; as well as other
compounds having diverse biological properties and structures.
It is also well-known that such prior art compounds are characterized by
certain inherent disadvantages, notably bioavailability problems upon
administration via oral, rectal or topical routes. The unionized form of a
drug is usually absorbed more efficiently than its ionic species and as
the carboxylic acid functional group is significantly ionized at
physiological pH, the result is that carboxylic acid agents are poorly
absorbed through lipid-water membrane barriers. In addition, by suffering
from reduced bioavailability, some acidic drugs, notably non-steroidal
anti-inflammatory agents (ibuprofen, tolmetin, naproxen, indomethacin,
etc.), are irritating to the mucous membrane of the gastro-intestinal
tract.
A promising approach to solve such problems may be esterification of the
carboxylic acid function to produce lipophilic and non-irritating prodrug
forms, provided that the biologically active parent drug can be released
from the prodrug form at its sites of activity. However, several aliphatic
or aromatic esters of carboxylic acid drugs are not sufficiently labile in
vivo to ensure a sufficiently high rate and extent of prodrug conversion.
For example, simple alkyl and aryl esters of penicillins are not
hydrolyzed to active free penicillin acid in vivo (Holysz & Stavely, 1950)
and therefore have no therapeutic potential (Ferres, 1983). Similarly, the
much reduced anti-inflammatory activity observed for the methyl or ethyl
esters of naproxen (Harrison et al., 1970) and fenbufen (Child et al.,
1977) relative to the free acids may be ascribed to the resistance of the
esters to be hydrolyzed in vivo. In the field of angiotensin-converting
enzyme inhibitors ethyl esters have been developed as prodrugs for the
parent active carboxylic acid drugs in order to improve their oral
bioavailability. Enalapril is such a clinically used ethyl ester prodrug
of enalaprilic acid. Plasma enzymes do not hydrolyze the ester and the
necessary conversion of the ester to the free acid predominantly takes
place in the liver (Tocco et al., 1982; Larmour et al., 1985). As recently
suggested (Larmour et al., 1985), liver function may thus be a very
important determinant for the bioactivation of enalapril and hence its
therapeutic effect. The limited susceptibility of enalapril to undergo
enzymatic hydrolysis in vivo has been shown to result in incomplete
availability of the active parent acid (Todd & Heel, 1986). Pentopril is
another ethyl ester prodrug of an angiotensin-converting enzyme inhibitor
which also is highly stable in human plasma. In this case less than 50% of
an oral dose of the prodrug ester appears to be deesterified in vivo to
the active parent acid (Rakhit & Tipnis, 1985).
As has been demonstrated in the case of penicillins (Ferres, 1983) these
shortcomings of some ester prodrugs may be overcome by preparing a double
ester type, acyloxyalkyl or alkoxycarbonyloxyalkyl esters, which in
general show a higher enzymatic lability than simple alkyl esters. The
general utility of this double ester concept in prodrug design is,
however, limited by the poor water solubility of the esters of several
drugs and the limited stability of the esters in vitro. In addition, such
esters are oils in many cases, thus creating pharmaceutical formulation
problems.
In view of the foregoing, it is quite obvious that a clear need exists for
new ester prodrug types possessing a high susceptibility to undergo
enzymatic hydrolysis in plasma or blood and further more being
characterized by providing ample possibilities for varying or controlling
the water and lipid solubilities.
In accordance with the present invention it has now been discovered that
esters of the formula I below are surprisingly rapidly cleaved
enzymatically in vivo, e.g. by plasma enzymes, and fulfil the
above-discussed desirable attributes.
A few compounds related to certain compounds of formula I have been
reported in the literature. Thus, Boltze et al. (1980) have described
various N-unsubstituted and N-monosubstituted
2-[1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetyloxy]-acetamide
derivatives having anti-inflammatory properties. Similarly, some acetamide
derivatives of flufenamic acid have been reported by Boltze & Kreisfeld
(1977). 2-[2-(Acetyloxy)benzoyloxy]-acetamide and other related ester
derivatives of acetylsalicylic acid are disclosed in Ger. Offen.
2,320,945.
However, there is no suggestion that the compounds described have any
prodrug activity, and enzymatic hydrolysis of the compounds into the
parent carboxylic acid drugs is neither explicitly nor implicitly
mentioned.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a novel ester prodrug
type characterized by possessing a high susceptibility to undergo
enzymatic hydrolysis in vivo and at the same time providing ample
possibilities for varying the water and lipid solubilities of the
derivatives.
It is another object of the present invention to provide novel
bioreversible derivatives for drugs or biologically active agents having a
carboxylic acid function which derivatives, when administered to
warm-blooded animals, e.g. humans, elicit the
bio-affecting/pharmacological response characteristic of the acids from
which they are derived, yet which are characterized in being less
irritating to topical and gastric or intestinal mucosal membranes.
It is another object of this invention to provide prodrugs of carboxylic
acid agents which are capable of providing increased biomembrane transport
so that the parent drugs are more bioavailable from the site of
administration such as the gastro-intestinal tract, the rectum, the skin
or the eye of the human body.
It is a further object of the present invention to provide such derivatives
of conventional carboxylic acids which are prodrugs designed to cleave in
such a manner as to enable the original parent drug form to be released at
its therapeutic site or sites of activity, while the remaining cleaved
moiety is non-toxic and/or is metabolized in a nontoxic fashion.
It is still another object of this invention to provide prodrug compounds
which utilize hydrolytic enzymes to generate the parent carboxylic
acid-type drug from the prodrug form.
It is yet another object of the present invention to provide derivatives of
carboxylic acid agents which derivatives are "soft" in nature, i.e., which
are characterized by in vivo destruction to essentially non-toxic
moieties, after they have achieved their desired therapeutic role (for
example, the compounds derived from steroidal acids of formula II below).
Other objects, features and advantages of the invention will be apparent to
those skilled in the art from the detailed description of the invention
which follows.
The foregoing objects, features and advantages are provided by the novel
compounds of the formula I
##STR2##
wherein R--COO-- represents the acyloxy residue of a carboxylic acid drug
or medicament,
n is an integer from 1 to 3, and
R.sub.1 and R.sub.2 are the same or different and are selected from a group
consisting of an alkyl group, an alkenyl group, an aryl group, an aralkyl
group, a cycloalkyl group, in which the alkyl, alkenyl, aryl, aralkyl or
cycloalkyl group is unsubstituted or substituted with one or more
substituents selected from:
a halogen atom,
a hydroxy group,
a carbonyl group,
a straight or branched-chain alkoxy group having the formula R.sub.3 --O--,
wherein R.sub.3 represents an alkyl group or an aryl group, which groups
may be unsubstituted or substituted with one or more of a halogen atom or
a hydroxy group,
a carbamoyl group having the formula
##STR3##
wherein R.sub.4 and R.sub.5 are the same or different and are hydrogen,
an alkyl group or are selected from a group having the formula --CH.sub.2
NR.sub.7 R.sub.6, wherein R.sub.6 and R.sub.7 are the same or different
and are hydrogen, an alkyl group, or together with the adjacent nitrogen
atom form a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition
to the nitrogen may contain one or two further heteroatoms selected from
the group consisting of nitrogen, oxygen, and sulfur,
an amino group having the formula --NR.sub.8 R.sub.9, wherein R.sub.8 and
R.sub.9 are the same or different and are hydrogen, an alkyl group or
together with the adjacent nitrogen atom form a 4-, 5-, 6- or 7-membered
heterocyclic ring, which in addition to the nitrogen may contain one or
two further heteroatoms selected from the group consisting of nitrogen,
oxygen, and sulfur,
an acyloxy group having the formula --COOR.sub.10, wherein R.sub.10 is an
alkyl, aryl or aralkyl group,
an oxyacyl group having the formula R.sub.11 COO-- wherein R.sub.11 is
hydrogen, an alkyl group, an aryl group, an aralkyl group, a cycloalkyl
group, in which the alkyl, aryl, aralkyl or cycloalkyl group is
unsubstituted or substituted with one or more of halogen atom, a hydroxy
group, an alkoxy group of the formula R.sub.3 --O-- as defined above, a
carbamoyl group of the formula --CONR.sub.4 R.sub.5 as defined above or an
amino group having the formula --NR.sub.8 R.sub.9 as defined above;
or R.sub.1 and R.sub.2 are combined so that --NR.sub.1 R.sub.2 forms a 4-,
5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen
atom may contain one or two further heteroatoms selected from the group
consisting of nitrogen, oxygen, and sulfur, and which heterocyclic ring
may be substituted with a hydroxy group, a carbonyl group, an alkyl group
or an oxyacyl group having the formula R.sub.11 COO--, wherein R.sub.11 is
as defined above, or an acyloxy group having the formula --COOR.sub.10,
wherein R.sub.10 is as defined above;
and nontoxic pharmaceutically acceptable acid addition salts thereof, with
the proviso that if R.sub.1 =alkyl then R.sub.2 =alkyl, and if R.sub.1
=CH.sub.2 CH.sub.2 OH then R.sub.2 =CH.sub.2 CH.sub.2 OH.
In the present context, the term "alkyl" designates C.sub.1-8 alkyl which
may be straight or branched, such as methyl, ethyl, propyl, isopropyl,
butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl. The term "alkenyl"
designates a C.sub.2-6 -monounsaturated aliphatic hydrocarbon group which
may be straight or branched, such as propenyl, butenyl or pentenyl. The
term "aryl" encompasses aryl radicals such as phenyl and naphthyl and also
the corresponding aryl radicals containing one or more substitutents,
which may be the same or different, such as alkylthio, alkyl, halogen,
alkoxy, nitro, alkanoyl, carbalkoxy, dialkylamino, alkanoyloxy or hydroxy
groups. The term "cycloalkyl" designates a radical containing 4 to 7
carbon atoms, e.g. cyclohexyl. The term "aralkyl" designates a radical of
the type -alkylene-aryl, wherein aryl is as defined above and the alkylene
moiety contains 1 to 6 carbon atoms and can be straight or branched-chain,
e.g. methylene, 1,2-butylene, and the like. When R.sub.1 and R.sub.2 in
the formula I, R.sub.4 and R.sub.5 in the formula --CONR.sub.4 R.sub.5
and R.sub.8 and R.sub.9 in the formula --NR.sub.8 R.sub.9 together with
the adjacent nitrogen atom form a 4-, 5-, 6- or 7-membered heterocyclic
ring which in addition to the nitrogen atom may contain 1 or 2 further
hetero atoms selected from the group consisting of nitrogen, oxygen, and
sulfur, it may, for instance, be 1-piperidinyl, 1-pyrrolidinyl,
1-piperazinyl, 4-methyl 1-piperazinyl, hexamethyleneimino, morpholinyl,
thiomorpholinyl, 1-pyrazolyl and 1-imidazolyl.
When one or more asymmetric carbon atoms are present in the R.sub.1 or
R.sub.2 groups as defined above, it is understood that the present
invention also encompasses all diastereomers or enantiomers, or mixtures
thereof. Examples of isomers are D-, L-, and DL- forms.
The term "non-toxic pharmaceutically acceptable acid addition salts" as
used herein generally includes the non-toxic acid addition salts of
compounds of formula I, formed with non-toxic inorganic or organic acids.
For example, the salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulphuric, sulphamic, nitric, phosphoric and
the like; and the salts with organic acids such as acetic, propionic,
succinic, fumaric, maleic, tartaric, citric, glycolic, lactic, stearic,
malic, pamoic, ascorbic, phenylacetic, benzoic, glutamic, salicylic,
sulphuric, sulphanilic, and the like.
As stated above, R--COO-- in formula I can represent the acyloxy residue of
any drug, pharmaceutical or medicament (R--COOH) having one or more
carboxylic acid functions. The chemical structure of the carboxylic acid
agents is not critical. Examples of drugs or pharmaceuticals from which
the instant prodrugs are derived include but are not limited to:
a. Non-steroidal anti-inflammatory agents like:
1 Acetylsalicylic acid (aspirin)
2. Salicylic acid
3. Sulindac
4. Indomethacin
5. Naproxen
6. Fenoprofen
7. Ibuprofen
8. Ketoprofen
9. Indoprofen
10. Furobufen
11. Diflunisal
12. Tolmetin
13. Flurbiprofen
14. Diclofenac
15. Mefenamic acid
16. Flufenamic acid
17. Meclofenamic acid
18. Fenclozic acid
19. Alclofenac
20. Bucloxic acid
21. Suprofen
22. Fluprofen
23. Cinchophen
24. Pirprofen
25. Oxoprozin
26. Cinmetacin
27. Acemetacin
28. Ketorolac
29. Clometacin
30. Ibufenac
31. Tolfenamic acid
32. Fenclofenac
33. Prodolic acid
34. Clonixin
35. Flutiazin
36. Flufenisal
37. Salicylsalicylic acid
38. O-(Carbamoylphenoxy)acetic acid
39. Zomepirac
40. Nifluminic acid
41. Lonazolac
42. Fenbufen
43. Carprofen
44. Tiaprofenic acid
45. Loxoprofen
46. Etodolac
47. Alminoprofen
48. 2-(8-Methyl-10,11-dihydro-11-oxodibenz[b,f]oxepin-2-yl)-propionic acid
49. 4-Biphenylacetic acid
b. Cephalosporin antibiotics like:
100. Cephalothin
101. Cephacetrile
102. Cephapirin
103. Cephaloridine
104. Cefazolin
105. Cefazuflur
106. Ceforanide
107. Cefazedone
108. Ceftezole
109. Cephanone
110. Cefotiam
111. Cefamandole
112. Cefonicid
113. Cefuroxime
114. Cefoperazone
115. Cefpiramide
116. Cefpimizole
117. Cefsulodin
118. Cefoxitin
119. Cefmetazole
120. Cefotetan
121. Cefbuperazone
122. Cefotaxime
123. Cefmenoxime
124. Ceftizoxime
125. Cefpirome
126. Ceftazidime
127. Cefodizime
128. Ceftriaxone
129. Latamoxef
130. Cephalexin
131. Cephradine
132. Cefaclor
133. Cefadroxil
134. Cefatrizine
135. Cefroxadine
136. Cephaloglycin
c. Penicillin antibiotics like:
200. Benzylpenicillin
201. Phenoxymethylpenicillin
202. Phenethicillin
203. Methicillin
204. Nafcillin
205. Oxacillin
206. Cloxacillin
207. Dicloxacillin
208. Flucloxacillin
209. Azidocillin
210. Ampicillin
211. Amoxycillin
212. Epicillin
213. Cyclacillin
214. Carbenicillin
215. Ticarcillin
216. Sulbenicillin
217. Azlocillin
218. Mezlocillin
219. Piperazillin
220. Apalcillin
221. Temocillin
222. Carfecillin
223. Carindacillin
224. Hetacillin
d. 4-Quinolone antibiotics like:
300. Ciprofloxacin
301. Norfloxacin
302. Acrosoxacin
303. Pipemidic acid
304. Nalidixic acid
305. Enoxacin
306. Ofloxacin
307. Oxolinic acid
308. Flumequine
309. Cinoxacin
310. Piromidic acid
311. Pefloxacin
e. Steroidal monocarboxylic acids having the structural formula II:
##STR4##
H wherein R.sub.20 is hydrogen, fluoro, chloro, or methyl; R.sub.21 is
hydrogen. fluoro or chloro; R.sub.22 is hydrogen, methyl, hydroxy or
--OCOR.sub.24 wherein R.sub.24 is C.sub.1 -C.sub.7 straight or branched
alkyl or phenyl; R.sub.23 is hydrogen, hydroxy, or --OCOR.sub.24 wherein
R.sub.24 is as defined above, with the proviso that when R.sub.22 is
hydroxy or --OCOR.sub.24 and R.sub.23 is other than hydrogen, then
R.sub.22 and R.sub.23 are identical; or R.sub.22 and R.sub.23 are combined
to form a divalent radical of the type
##STR5##
wherein R.sub.25 and R.sub.26, which can be the same or different are each
C.sub.1-7 straight or branched alkyl or phenyl; Z is carbonyl or
.beta.-hydroxymethylene; the wavy line at the 16-position indicates the
.alpha. or .beta.-configuration; and the dotted line in the ring A
indicates that the 1,2-linkage is saturated or unsaturated.
A particularly preferred group of carboxylic acids of the formula II
consists of the compounds wherein the structural variables represented by
R.sub.20, R.sub.21, R.sub.22, R.sub.23 and Z and the dotted and wavy lines
are identical to those of a known anti-inflammatory steroid selected from
the group consisting of hydrocortisone, betamethasone, dexamethasone,
prednisolone, triamcinolone, fluocortolone, cortisone, fludrocortisone,
chloroprednisone, flumethasone, fluprednisolone, meprednisone, methyl
prednisolone, paramethasone, prednison, flurandrenolone acetonide,
amcinafal, amcinafide, clocortolone, desonide, desoximetasone,
fifluprednate, flunisolide, fluocinolone acetonide. triamcinolone
acetonide, betamethasone 17-benzoate and betamethasone 17-valerate.
Another preferred group of compounds of formula II consists of the
compounds wherein the structural variables represented by R.sub.20,
R.sub.21, R.sub.22, Z and the dotted and wavy lines are identical to those
of a known anti-inflammatory steroid selected from the group consisting of
hydrocortisone, cortisone, fludrocortisone, betamethasone,
chloroprednisone, dexamethasone, flumethasone, fluprednisolone,
meprednisone, methyl prednisolone, paramethasone and prednisolone, and
R.sub.23 is --OCOR.sub.24 wherein R.sub.24 is as hereinbefore defined,
most especially when R.sub.24 is CH.sub.3, C.sub.2 H.sub.5, C.sub.3
H.sub.7 or phenyl. Yet another preferred group of parent acids of formula
II consists of the compounds wherein the structural variables represented
by R.sub.20, R.sub.21, Z and the wavy and dotted lines are identical to
those of triamcinolone, and R.sub.22 and R.sub.23 are identical
--OCOR.sub.24 groupings wherein R.sub.24 is as hereinbefore defined, most
especially when R.sub.24 is CH.sub.3, C.sub.2 H.sub.5, C.sub.3 H.sub.7 or
phenyl. Particularly preferred parent acids encompassed by formula II
include
6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxopregna-1,4-dien
-21-oic acid;
9.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.beta.-methyl-3,20-dioxopreg
na-1,4-dien-21-oic acid;
9.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-3,20-dioxopre
gna-1,4-dien-21-oic acid;
11.beta.,17.alpha.-dihydroxy-3,20-dioxopregn-4-en-21-oic acid;
9.alpha.-fluoro-11.beta.,16.alpha.,17.alpha.-trihydroxy-3,20-dioxopregna-1,
4-dien-21-oic acid; and
11.beta.,17.alpha.-dihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid;
as well as the corresponding 17-esters of the specific 17-hydroxy compounds
just named, most especially the 17-propionates, butyrates and benzoates
thereof.
f. Prostaglandins like:
500. Prostaglandin E.sub.2
501. Prostaglandin F.sub.2.alpha.
502. 15-Deoxy-16-hydroxy-16-vinylprostaglandin E.sub.2
503. 11-Deoxy-11.sub..alpha.,12.sub..alpha. -methanoprostaglandin E.sub.2
504. 11-Deoxy-11.sub..alpha.,12.sub..alpha. -difluoromethanoprostaglandin
E.sub.2
405. Prostacyclin
506. Epoprostenol
507. dl-16-Deoxy-16-hydroxy-16 (.alpha./.beta.)-vinyl prostaglandin E.sub.2
508. Prostaglandin E.sub.1
509. Thromboxane A.sub.2
510. 16,16-Dimethylprostaglandin E.sub.2
511. (15R) 15-Methylprostaglandin E.sub.2 (Arbaprostil)
512. Meteneprost
513. Nileprost
514. Ciprostene
g. Angiotensin-converting enzyme inhibitors like:
600. (2R,
4R)-2-(2-Hydroxyphenyl)3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic
acid
601. Enalaprilic acid
(N-[1-(S)-carboxy-3-phenyl-propyl]-L-alanyl-L-proline)
602. Captopril
603.
N-Cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]g
lycine
604.
1[4-Carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylic
acid
605. Alecapril
(1-[(S)-3-Acetylthio-2-methyl-propanoyl]-L-propyl-L-phenylalanine)
606.
[3S-[2[R*(R*)]],3R*]-2-[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]-
1, 2,3,4-tetrahydro-3-isoquinoline carboxylic acid
607. [2S-[1[R*(R*)]],2.alpha.,3.alpha..beta.,
7.alpha..beta.]-1[2-[[1-carboxy-3-phenylpropyl]-amino]-1-oxopropyl]octahyd
ro-1H-indole-2-carboxylic acid.
608. (S)-Benzamido-4-oxo-6-phenylhexanoyl-2-carboxy-pyrrolidine
609. Lisinopril
610. Tiopronin
611. Pivopril
h. Various other bio-affecting carboxylic acid agents:
700. Ethacrynic acid
701. L-Tyrosine
702. .alpha.-Methyl-L-tyrosine
703. Penicillamine
704. Probenicid
705. 5-Aminosalicylic acid
706. 4-Aminobenzoic acid
707. Methyldopa
708. L-Dopa
709. Carbidopa
710. Valproic acid
711. 4-Aminobutyric acid
712. Moxalactam
713. Clavulanic acid
714. Tranexamic acid
715. Furosemide
716. 7-Theophylline acetic acid
717. Clofibric acid
718. Thienamycin
719. N-Formimidoylthienamycin
720. Amphotericin B
721. Nicotinic acid
722. Methotrexate
723. L-Thyroxine
724. Cromoglycic acid
725. Bumetanide
726. Folic acid
727. Chlorambucil
728. Melphalan
729. Fusidic acid
730. 4-Aminosalicylic acid
731. Liothyronine
732. Tretinoin
733. o-Thymotinic acid
734. 6-Aminocaproic acid
735. L-Cysteine
736. Tranilast (N-(3',4'-dimethoxycinnamoyl)anthranilic acid)
737. Baclofen
738. 4-Amino-5-ethyl-3-thiophenecarboxylic acid
739.
N-Cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]2-methyl-1-oxopropyl]gl
ycine
740. Isoguvacine
741. Nipecotic acid
742. D-Eritadenine [(2R,3R)-4-adenin-9-yl-2,3-dihydroxybutanoic acid]
743. (RS)-3-Adenin-9-yl-2-hydroxypropanoic acid
744.
1-[4-Carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylic
acid
745. Phenylalanylalanine
746. Glafenic acid
747. Floctafenic acid
748. N-(Phosphonoacetyl)-L-aspartic acid (PALA)
749. Proxicromil
750. Cysteamine
751. N-Acetylcysteine
752. Proglumide
753. Aztreonam
754. Mecillinam
755. All-trans-retinoic acid
756. 13-cis-retinoic acid
757. Isonipecotic acid
758. Anthracene-9-carboxylic acid
759. .alpha.-Fluoromethylhistidine
760. 6-Amino-2-mercapto-5-methylpyrimidine-4-carboxylic acid
761. Glutathione
762. Acivicin
763. L-.alpha.-Glutamyl dopamine
764. 6-Aminonicotinic acid
765. Loflazepate
766. 6-[[1(S)-[3(S),4-dihydro-8-hydroxy-1-oxo-1
H-2-benzopyran-3-yl]-3-methylbutyl]amino]-4-(S),5(S)-dihydroxy-6-oxo-3(S)-
ammoniohexanoate
767. Z-2-Isovaleramidobut-2-enoic acid
768. D,L-2,4-Dihydroxyphenylalanine
769. L-2-Oxothiazolidine-4-carboxylic acid
770. Iopanoic acid
771. 4-Aminomethylbenzoic acid
772. 4-Hydroxybenzoic acid
773. 4-Hydroxybutyric acid
774. Ticrynafen
775. 4-amino-3-phenylbutyric acid
776. 4-(Dimethylamino)benzoic acid
777. Capobenic acid
778. Pantothenic acid
779. Folinic acid
780. Orotic acid
781. Biotin
782. Mycophenolic acid
783. Thioctic acid
784. Pyroglutamic acid
785. Oleic acid
786. Linoleic acid
787. Cholic acid
788. Naturally occurring amino acids (e.g. glycine, histidine,
phenylalanine and glutamic acid)
789. N,N-Dimethylglycine
790. Salazosulfapyridine
791. Azodisal
792. lsotretinoin
793. Etretinic acid
All of the above compounds are known in the art in the acid or salt form.
While all of the compounds encompassed by formula 1 essentially satisfy the
objectives of the present invention, preferred compounds include those
derived from the following compounds (compounds A)
1. Acetylsalicylic acid
2. Salicylic acid
3. Sulindac
4. Indomethacin
5. Naproxen
7. Ibuprofen
8. Ketoprofen
11. Diflunisal
12. Tolmetin
13. Flurbiprofen
15. Mefenamic acid
21. Suprofen
31. Tolfenamic acid
119. CefmerazoIe
104. Gefazolin
130. Cephalexin
132. Cefaclor
133. Cefuroxime
134. Cefamandole
118. Cefoxitin
200. Benzylpenicillin
201. Phenoxymethylpenicillin
210. Ampicillin
211. Amoxycillin
214. Carbenicillin
217. Azlocillin
219. Piperacillin
6.alpha.-Fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxopregna-1,4-dien
-21-oic acid
9.alpha.-Fluoro-11.beta.,17.alpha.-dihydroxy-16.beta.-methyl-3,20-dioxopreg
na-1,4-dien-21-oic acid
9.alpha.-Fluoro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-3,20-dioxopre
gna-1,4-dien-21-oic acid
11.beta., 17.alpha.-Dihydroxy-3,20-dioxopregn-4-en-21-oic acid
9.alpha.-Fluoro-11.beta.,16.alpha.,17.alpha.-trihydroxy-3,20-dioxopregna-4-
dien-21-oic acid
11.beta.,17.alpha.-Dihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid.
500. Prostaglandin E.sub.2
501. Prostaglandin F.sub.2.alpha.
508. Prostaglandin E.sub.1
505. Prostacyclin
511. (15R)-15-Methylprostaglandin E.sub.2 (Arbaprostil)
513. Nileprost
514. Ciprostene
601. Enalaprilic acid
602. Captopril
603.
N-Cyclopentyl-N-[3[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]gl
ycine
604.
1-[4-Carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylic
acid
607. [2S
[1[R*(R*)]],2.alpha.,3.alpha..beta.,7.alpha..beta.]-1-[2-[[1-carboxy-3-phe
nylpropyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylc acid
705. 5-Aminosalicylic acid
707. Methyldopa
708. L-Dopa
710. Valproic acid
714. Tranexamic acid
715. Furosemide
722. Methotrexate
727. Chlorambucil
717. Clofibric acid
720. Amphotericin B
734. 6-Aminocaproic acid
754. Mecillinam
732. Tretinoin
771. 4-Aminomethylbenzoic acid
782. Mycophenolic acid
768. D,L-2,4-Dihydroxyphenylalanine
Particularly preferred compounds of the invention include those wherein
R--COO is derived from one of the specific bio-affecting acids named
above, n is 1 and R.sub.1 and R.sub.2 are as defined in connection with
the general formula I.
In especially preferred compounds of the formula I, R--COO is derived from
one of the compounds A above, n=1, and
R.sub.1 =CH.sub.3 or C.sub.2 H.sub.5,
##STR6##
It will be appreciated that in the especially preferred compounds defined
immediately above, each and every possible combination between the given
examples of R.sub.1 and R.sub.2 in the derivative group --CH.sub.2
CONR.sub.1 R.sub.2 may, of course, be combined with each and every group
R--COO derived from the compounds A listed above, and that the above
definition is equivalent to listing each and every possible combination of
the listed examples of R--COO, R.sub.1 and R.sub.2.
The invention further concerns compounds of the general formula I as
defined above wherein R.sub.1 and R.sub.2 both are alkyl or both are
--CH.sub.2 CH.sub.2 OH, and
R--COO-- is the acyloxy residue of one of the following bio-affecting
carboxylic acid agents (compounds B)
2. Salicylic acid
3. Sulindac
4. Indomethacin
5. Naproxen
7. Ibuprofen
8. Ketoprofen
11. Diflunisal
12. Tolmetin
13. Flurbiprofen
15. Mefenamic acid
21. Suprofen
31. Tolfenamic acid
119. Cefmetazole
104. Cefazolin
130. Cephalexin
132. Cefaclor
133. Cefuroxime
134. Cefamandole
118. Cefoxitin
200. Benzylpenicillin
201. Phenoxymethylpenicillin
210. Ampicillin
211. Amoxycillin
214. Carbenicillin
217. Azlocillin
219. Piperacillin
6.alpha.-Fluoro-11.beta.-hydroxy-16.alpha.-methyl-3,20-dioxopregna-1,4-dien
-21-oic acid
9.alpha.-Fluoro-11.beta.,17.alpha.-dihydroxy-16.beta.-methyl-3,20-dioxopreg
na-1,4-dien-21-oic acid
9.alpha.-Fluoro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-3,20-dioxopre
gna-1,4-dien-21-oic acid
11.beta.,17.alpha.-Dihydroxy-3,20-dioxopregn-4-en-21-oic acid
9.alpha.-Fluoro-11.beta.,16.alpha.,17.alpha.-trihydroxy-3.20-dioxopregna-4-
dien-21-oic acid
11.beta.,17.alpha.-Dihydroxy-3,20-dioxopregna-1,4-dien-21-oic acid.
500. Prostaglandin E.sub.2
501. Prostaglandin F.sub.2.alpha.
508. Prostaglandin E.sub.1
505. Prostacyclin
511. (15R)15-Methylprostaglandin E.sub.2 (Arbaprostil)
513. Nileprost
514. Ciprostene
601. Enalaprilic acid
602. Captopril
603.
N-Cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1-oxopropyl]g
lycine
604.
1-[4-Carboxy-2-methyl-2R,4R-pentanoyl]-2,3-dihydro-2S-indole-2-carboxylic
acid
607.
[2S-[1[R*(R*)]],2.alpha.,3.alpha..beta.,17.alpha..beta.]-1-[2-[[1-carboxy-
3-phenylpropyl]amino]-1-oxopropyl]octahydro-1H-indole-2-carboxylic acid
705. 5-Aminosalicylic acid
707. Methyldopa
708. L-Dopa
710. Valproic acid
714. Tranexamic acid
715. Furosemide
722. Methotrexate
727. Chlorambucil
717. Clofibric acid
720. Amphotericin B
734. 6-Aminocaproic acid
754. Mecillinam
732. Tretinoin
771. 4-Aminomethylbenzoic acid
782. Mycophenolic acid
768. D,L-2,4-Dihydroxyphenylalanin
When R.sub.1 and R.sub.2 are both alkyl, they may be the same or different
and are preferably C.sub.1-3 alkyl such as methyl, ethyl, n-propyl or
isopropyl. It is further preferred that n=1. It will be appreciated that
in such preferred compounds, each and every possible combination of
R.sub.1 and R.sub.2 (i.e. both being --CH.sub.2 CH.sub.2 OH, or R.sub.1
and R.sub.2 individually being selected from methyl, ethyl, propyl and
isopropyl) in the derivative group --CH.sub.2 CONR.sub.1 R.sub.2 may, of
course, be combined with each and every group R--COO derived from the
compounds B listed above, and that the above definition is equivalent to
listing each and every possible combination of the listed examples of
R--COO (from compounds B), R.sub.1 and R.sub.2.
DETAILED DESCRIPTION OF THE INVENTION
DOSAGE FORMS AND DOSE
The prodrug compounds of formula I of the present invention can be used to
treat any condition for which the parent carboxylic group containing drug,
medicament or pharmaceutical is useful. For example, if naproxen is the
parent drug of choice, the ester prodrug can be used for any condition or
treatment for which naproxen would be administered.
Thus, the prodrug compounds of formula I may be administered orally,
topically, parenterally, rectally or by inhalation spray in dosage forms
or formulations containing conventional, non-toxic pharmaceutically
acceptable carriers, adjuvants and vehicles. The formulation and
preparation of any of this broad spectrum of dosage forms into which the
subject prodrugs can be disposed is well-known to those skilled in the art
of pharmaceutical formulation. Specific information can, however, be found
in the text entitled "Remington's Pharmaceutical Sciences", Sixteenth
Edition, 1980.
The pharmaceutical compositions containing the active ingredient may be in
a form suitable for oral use, for example, as tablets, troches, lozenges,
aqueous or oily suspensions, dispersible powders or granules, emulsions,
hard or soft capsules, or syrups or elixirs. Compositions intended for
oral use may be prepared according to any method known in the art for the
manufacture of pharmaceutical compositions and such compositions may
contain one or more agents selected from the group consisting of
sweetening agents, flavouring agents, colouring agents and preserving
agents in order to provide a pharmaceutically elegant and palatable
preparation.
Formulations for oral use include tablets which contain the active
ingredient in admixture with non-toxic pharmaceutically acceptable
excipients. These excipients may be, for example, inert diluents, such as
calcium carbonate, sodium chloride, lactose, calcium phosphate or sodium
phosphate; granulating and disintegrating agents, for example, potato
starch, or alginic acid; binding agents, for example, starch, gelatin or
acacia; and lubricating agents, for example, magnesium stearate, stearic
acid or talc. The tablets may be uncoated or they may be coated by known
techniques to delay disintegration and absorption in the gastrointestinal
tract and thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or glyceryl
distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules
wherein the active ingredient is mixed with an inert solid diluent, for
example, calcium carbonate, calcium phosphate or kaolin, or as soft
gelatin capsules wherein the active ingredient is mixed with water or an
oil medium, for example, peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions usually contain the active materials in admixture with
appropriate excipients. Such excipients are suspending agents, for
example, sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum
tragacanth and gum acacia; dispersing or wetting agents which may be a
naturally-occurring phosphatide, for example, lecithin; a condensation
product of an alkylene oxide with a fatty acid, for example,
polyoxyethylene stearate; a condensation product of ethylene oxide with a
long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol; a
condensation product of ethylene oxide with a partial ester derived from
fatty acids and a hexitol such as polyxyethylene sorbitol monooleate; or a
condensation product of ethylene oxide with a partial ester derived from
fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan
monooleate. The aqueous suspensions may also contain one or more
preservatives, for example, methyl, ethyl or n-propyl p-hydroxybenzoate;
one or more colouring agents; one or more flavouring agents; and one or
more sweetening agents such as sucrose or saccharin.
Oily suspension may be formulated by suspending the active ingredient in a
vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut
oil, or in a mineral oil such as liquid paraffin. The oily suspensions may
contain a thickening agent, for example, beeswax, hard paraffin or cetyl
alcohol. Sweetening agents such as those set forth above, and flavouring
agents may be added to provide a palatable oral preparation. These
compositions may be preserved by the addition of an antioxidant such as
ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water provide the active ingredient in
admixture with a dispersing or wetting agent, suspending agent and one or
more preservatives. Suitable dispersing or wetting agents and suspending
agents are exemplified by those already mentioned above. Additional
excipients, for example, sweetening, flavouring and colouring agents, may
also be present.
The pharmaceutical compositions of the invention may also be in the form of
oil-in-water emulsions. The oily phase may be a vegetable oil, for
example, olive oil or arachis oils, or a mineral oil, for example, liquid
paraffin or mixtures of these. Suitable emulsifying agents may be
naturally-occurring gums, for example, gum acacia or gum tragacanth;
naturally-occurring phosphatides, for example, soybean licithin; and
esters including partial esters derived from fatty acids and hexitol
anhydrides, for example, sorbitan mono-oleate, and condensation products
of the said partial esters with ethylene oxide, for example,
polyoxyethylene sorbitan monooleate. The emulsions may also contain
sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example
glycerol, sorbitol or sucrose. Such formulations may also contain a
demulcent, a preservative and flavouring and colouring agents, The
pharmaceutical compositions may be in the form of a sterile injectable
aqueous or oleagenous suspension. This suspension may be formulated
according to the known art using those suitable dispersing or wetting
agents and suspending agents which have been mentioned above. The sterile
injectable preparation may be a sterile injectable solution or suspension
in a non-toxic parenterally acceptable diluent or solvent. Among the
acceptable vehicles and solvents that may be employed are water,
1,3-butanediol, Ringer's solution and isotonic sodium chloride solution.
In addition, sterile fixed oils are conventionally employed as a solvent
or suspending medium. For this purpose any bland fixed oil may be employed
including synthetic monoor diglycerides. Fatty acids such as oleic acid
also find use in the preparation of injectibles.
The compounds of formula I may also be administered in the form of
suppositories for rectal administration of the drug. These compositions
can be prepared by mixing the drug with a suitable nonirritating excipient
which is solid at ordinary temperatures but liquid at the rectal
temperature and will therefore melt in the rectum to release the drug, for
example, cocoa butter, or adeps solidus polyethylene glycols.
For topical use, creams, ointments, jellies, solutions, suspensions or the
like containing the prodrugs are employed according to methods recognized
in the art.
Naturally, therapeutic dosage range for the compounds of the present
invention will vary with the size and needs of the patient and the
particular pain or disease symptom being treated. However, generally
speaking, the following dosage guidelines will suffice. On an oral basis,
the therapeutic dose required for a compound of the present invention will
generally, on a molecular basis, mimic that for the parent carboxylic acid
drug. On a topical basis, application of an 0.01% to 5% concentration of a
compound of the present invention (in a suitable topical carrier material)
to the affected site should suffice.
From the foregoing description, one of ordinary skill in the art can easily
ascertain the essential characteristics of the present invention and,
without departing from the spirit and scope thereof, can make various
changes and/or modifications of the invention to adapt it to various
usages and conditions. As such, these changes and/or modifications are
properly, equitably and intended to be within the full range of
equivalence of the following claims.
The amount of active ingredient that may be combined with the carrier
materials to produce a single dosage form will vary depending upon the
host treated and the particular mode of administration. For example, a
formulation intended for the oral administration of humans may contain
from 5 mg to 5 gm of the active agent compounded with an appropriate and
convenient amount of carrier material which may vary from about 5 to about
95% of the total composition. Other dosage forms such as ophthalmic dosage
forms contain less active ingredient such as for example from 0.1 mg to 5
mg. Dosage unit forms will generally contain between from about 0.1 mg to
about 500 mg of active ingredient.
It will be understood, however, that the specific dose level for any
particular patient will depend upon a variety of factors including the
activity of the specific compound employed, the age, body weight, general
heath, sex, diet, time of administration, route of administration, rate of
excretion, drug combination and severity of the particular disease
undergoing therapy.
PREPARATION OF THE PRODRUGS OF FORMULA I
The compounds of the present invention can be prepared by a variety of
synthetic routes. A generally applicable process (method a) comprises
reacting the carboxylic acid agent of the formula A or a salt (e.g. a
metal salt) thereof
R--COOH (A)
wherein R--COO-- is defined as above in connection with formula I, with a
compound having the formula B:
##STR7##
wherein n, R.sub.1 and R.sub.2 are as defined above and X is a suitable
leaving group (e.g., halogen such as Cl, I or Br, or a methansulfonyloxy
or toluenesulfonyloxy group). The reaction is preferably carried out in a
solvent (e.g. N,N-dimethylformamide, water, acetonitrile, a lower alcohol,
ethyl acetate, toluene or the like). An equivalent of an organic base such
as triethylamine, tetramethylguanidine or the like is typically added or
crown ethers are used as phase-transfer catalysts. If X in formula B is
chlorine catalytic amounts of an iodide salt may be added to the reaction
mixture. The reaction is carried out at a temperature of from room
temperature to the boiling point of the solvent, and for a period of time
of 0.5 to 48 hours.
Another method (method b) for preparing compounds of the invention
comprises reacting a compound of the formula B, wherein X is hydroxy, with
an acid of the formula A or with the corresponding acid chloride of the
formula C
R--COCl (C)
When an acid starting material is used, i.e. a compound of formula A, the
reaction is conducted in the presence of a suitable dehydrating agent, for
example N,N-dicyclohexylcarbodiimide. The reaction utilizing an acid
starting material is conveniently carried out in an inert solvent such as
dichloromethane, dioxane, pyridine or the like, at a temperature of from
0.degree. to 60.degree. C., for from 1 to 48 h. A catalyst such as
p-toluenesulphonic acid or 4-(N,N-dimethylamino)pyridine may be added.
When the reaction utilizes an acid chloride starting material, the process
can be conveniently carried out by reacting the compound of formula B,
wherein X is hydroxy, with the desired acid chloride in an inert solvent
such as benzene, dichloromethane, dimethylformamide, acetone, dioxane,
acetonitrile or the like, at from room temperature to reflux, for from 1
to 24 h, in the presence of an acid scavenger such as an alkali metal
carbonate, or an organic base such as triethylamine or pyridine.
The acid chlorides of formula C which can be used in the above method are
prepared from the corresponding acids by known means. e.g. by treatment of
the acid with thionyl chloride or oxalyl chloride. Instead of acid
chlorides acid anhydrides or mixed anhydrides may be used.
The starting materials of formula B, in which X is a halogen, are also
prepared by known means, e.g. by treatment of the appropriate amine with
an appropriately halogen-substituted acid chloride, acid anhydride or
ester as represented by the following chemical equation for an acid
chloride:
R.sub.1 R.sub.2 NH+X--(CH.sub.2).sub.n COCl.fwdarw.X--(CH.sub.2).sub.n
CONR.sub.1 R.sub.2
Several compounds of formula B, in which X is a halogen, and methods for
their preparation, have been described in the literature, see e.g. Hankins
(1965), Weaver and Whaley (1947), Ronwin (1953), Berkelhammer et al.
(1961) and Speziale and Hamm (1956).
The starting materials of formula B, in which X is hydroxy, are also
prepared by known means, e.g. by hydrolysis of 2-(acetoxymethyl)acetamides
or 2-(benzoyloxymethyl)acetamides. Specific examples are given below.
Several compounds of formula B, in which X is hydroxy, and methods for
their preparation, have been described in the literature, see e.g. DE
Offen. 2,904,490, DE 2,201,432, and DE 2,219,923.
A third method (method c) for preparing compounds of the present invention
comprises reacting a compound of the formula D
HNR.sub.1 R.sub.2 (D)
wherein R.sub.1 and R.sub.2 are as defined above in connection with formula
I, with an acid of the formula E
R--COO(CH).sub.n COOH (E)
wherein R--COO-- and n are as defined above in connection with formula I,
or with the corresponding acid chloride (or acid anhydrides) of the
formula F
R--COO(CH.sub.2).sub.n COCl (F)
When a compound of formula E is used, the reaction is conducted in the
presence of a suitable dehydrating agent, e.g.
N,N-dicyclohexylcarbodiimide. The reaction is conveniently carried out in
an inert solvent such as dichloromethane, dioxane, pyridine or the like,
at a temperature of from 0.degree. to 60.degree. C., for from 1 to 48 h.
When the reaction utilizes an acid chloride starting material of formula
F, the process can be conveniently carried out by reacting the compound of
formula F with the desired amine or amine salt in a solvent such as
benzene, dichloromethane, dimethylformamide, acetone, dioxane,
acetonitrile, water or the like, at from 0.degree. C. to reflux, for from
1/2 to 24 h, in the presence of an acid scavenger such as alkali metal
carbonate, or an organic base such as triethylamine, or an excess of the
amine.
The acid chlorides of formula F which can be used in the above method are
prepared from the corresponding acids by known means. e.g. by treatment of
the acid with thionyl chloride or oxalyl chloride.
The acids of formula E which can be used in the above method are prepared
from the parent acids (i.e. R--COOH) by known means, e.g. by reacting the
acid or a salt of the acid (e.g. a metal or trimethylammonium salt) with
compounds of the formula G
X--(CH.sub.2).sub.n COOCH.sub.2 C.sub.6 H.sub.5 (G)
wherein X and n are as defined above, or with compounds of the formula H
X--(CH.sub.2).sub.n CONH.sub.2 (H)
wherein X and n are as defined above. The intermediates obtained therefrom,
i.e. R--COO--(CH.sub.2).sub.n COOCH.sub.2 C.sub.6 H.sub.5 and
R--COO--(CH.sub.2).sub.n --CONH.sub.2, are subsequently transformed to the
compounds of formula E by e.g. hydrogenation or acidic hydrolysis. Several
compounds of formula E and methods for preparing them are known from the
literature, see e.g. Boltze et al. (1980) and Concilio & Bongini (1966).
While the basic methods described above can be used to prepare any of the
compounds of the invention, certain conditions and/or modifications
therein are made in specific instances. Thus, for example, the basic
methods may be modified in the cases where the desired product of formula
I contains free aliphatic amino, thiol or hydroxyl groupings which, if
present in the acid starting material, would undergo undesired side
reaction and/or would interfere with the desired course of the
above-described ester formation. In such cases, the compounds of formula B
or D are reacted with an acid of the formula J
R.sup.1 --COOH (J)
wherein R.sup.1 --COO-- is the amino-, thiol- or hydroxyl-protected acyloxy
residue of a carboxylic acid agent (R--COOH) containing amino, thiol or
hydroxyl groups. The amino, hydroxy or thiol function in the parent acids
of the formula RCOOH are converted to their protected counterparts in
formula J by known methods, e.g. those known in the art of peptide
synthesis. For example, amino groups are conveniently protected by the
carbobenzoxycarbonyl or t-butyloxycarbonyl group. The compound of formula
J, its corresponding acid chloride or protected counterpart for formula E
is subsequently reacted with a compound of formula B or D, as described
supra, to afford the compound corresponding to formula I, but containing a
protected acyloxy residue, i.e. R.sup.1 --COO-- as defined above in place
of R--COO-- in formula I. That protected compound is then deprotected by
known methods, e.g. by hydrogenation or hydrolysis.
The above-described process variations involving the addition and ultimate
removal of protecting groups is only used when the free amino, hydroxy
and/or thiol functions are in need of protection.
When the starting acid of formula I hereinabove is a steroidal acid of
formula II, this can be prepared by methods known in the art, for example
by the methods described in U.S. Pat. No. 4,164,504 (Varma). See also
Chemical Abstracts, 83, 179407 and 84, 122146. Thus, the following
reaction scheme is illustrative of a general method for preparing the
desired acids:
##STR8##
wherein R.sub.20, R.sub.21, R.sub.22, R.sub.23, Z and the dotted and wavy
lines are defined as before. In the cupric acetate reaction, water is used
as a co-solvent with a suitable alcohol, e.g. methanol or other lower
alkanol, and the reaction is allowed to proceed for an extended period of
time (more than 24 hours), since decreasing the water present and
lessening reaction time tend to favour formation of the 21-ester of the
steroid with the alcohol employed. Also, oxygen or air is bubbled through
the mixture during the course of the reaction to encourage formation of
21-acid rather than 21-aldehyde. In the second step, the 20-hydroxy group
is oxidized to a 20-keto function by reacting the steroid of formula XXI
with manganese dioxide or lead dioxide in an inert halogenated hydrocarbon
solvent such as chloroform or dichloromethane.
DESCRIPTION OF THE DRAWINGS
FIG. 1 shows time courses for naproxen N,N-dimethylglycolamide ester ( )
and naproxen (.smallcircle.) during hydrolysis of the ester in 80% human
plasma at 37.degree. C. The initial ester concentration was 10.sup.-4 M.
FIG. 2 shows plots of the first-order kinetics of hydrolysis of various
esters (initial concentration being 10.sup.-4 M) in 80% human plasma at
37.degree. C. Key: o, N,N-diethylglycolamide ester of L-phenylalanine; ,
N,N-diethylglycolamide ester of naproxen; .DELTA., N-methyl,
N-carbamoylmethylglycolamide ester of ketoprofen.
FIG. 3 shows plot of the rate of hydrolysis of the N,N-dimethylglycolamide
ester of salicylic acid in 80% human plasma at 37.degree. C.
the present invention is further illustrated by the following examples
which, however, are not construed to be limiting. The derivatives
described all had spectroscopic properties (IR and .sup.1 H NMR) and
elemental analysis (C, H and N) in agreement with their structures.
EXAMPLE 1
2(BENZOYLOXY)-N,N-DIMETHYLACETAMIDE
Benzoic acid (2.44 g, 0.02 mole) and 2-chloro-N,N-dimethylacetamide (2.43
g, 0.02 mole) were dissolved in 10 ml of N,N-dimethylformamide. Sodium
iodide (150, 2 mmol) and triethylamine (2.02 g, 0.02 mole) were added and
the mixture was stirred at room temperature (20.degree.-25.degree. C.)
overnight. After addition of 50 ml of water the reaction mixture was
extracted twice with ethyl acetate. The combined extracts were washed with
a diluted solution of sodium thiosulphate, a 2% aqueous solution of sodium
bicarbonate, water, dried over anhydrous sodium sulphate and evaporated in
vacuo. The residue was crystallized from ethanol-water to give 3.5 g (85%)
of the title compound. Mp 81.degree.-82.degree. C.
EXAMPLE 2
The compound in Example 1 was also prepared by the following procedure:
2-Chloro-N,N-dimethylacetamide (12.16 g, 0.1 mole) was added to a solution
of sodium benzoate (14.4 g, 0.1 mole) and sodium iodide (3.75 g, 0.025
mole) in 75 ml of water. The reaction solution was refluxed for 2 h. Upon
standing overnight at 4.degree. C. the title compound precipitated. It was
filtered off, washed with water and recrystallized from aqueous ethanol
(15.7 g; 76%). Mp 83.degree.-82.degree. C.
EXAMPLE 5
(BENZOYLOXY)ACETYL CHLORIDE
2-Chloroacetamide (18.7 g, 0.2 mole) was added to a solution of sodium
benzoate (28.8 g, 0.2 mole) and sodium iodide (7.5 g, 0.05 mole) in 150 ml
of water. The mixture was stirred at 90.degree. C. for 14 h.
Upon cooling to 4.degree. C. 2-(benzoyloxy)acetamide precipitated and was
isolated by filtration. Recrystallization from ethanol-water yielded 32.2
g (90%). Mp 120.5.degree.-121.degree. C.
2-(Benzoyloxy)acetamide (19.7 g, 0.11 mole) was added to 200 ml of 7.8M
hydrochloric acid. The mixture was stirred at 75.degree. C. for 10 min.
Upon cooling 2-(benzoyloxy)acetic acid precipitated. It was isolated by
filtration, dried and recrystallized from benzene (15.8 g, 80%), M.
111.degree.-112.degree. C.
A mixture of 2-(benzoyloxy)acetic acid (12.6 g) and thionyl chloride (15
ml) was refluxed for 3 h. Excess of thionyl chloride was removed in vacuo
and the crude (benzoyloxy)acetyl chloride obtained was purified by
distillation in vacuo. The yield was 88%. Mp 25.degree.-26.degree. C.
EXAMPLE 4
2-(BENZOYLOXY)-(N-METHYL-N-ETHOXYCARBONYLMETHYL)ACETAMIDE
A solution of (benzoyloxy)acetyl chloride (0.8 g , 4 mmole) in 4 ml of
benzene was added to a cooled (about 5.degree. C.) solution of sarcosine
ethyl ester hydrochloride (0.894 g, 12 mmole) in 6 ml of 2M sodium
hydroxide. The mixture was stirred vigorously at room temperature for 2 h.
The layers were separated and the aqueous phase re-extracted with ethyl
acetate (20 ml). The combined organic extracts were washed with 2M
hydrochloric acid (10 ml), and dried. Evaporation in vacuo afforded an
oily residue which crystallized by trituration with petroleum ether at
-20.degree. C.
Recrystallization from ether-petroleum ether yielded the title compound
(0.68 g, 61%). Mp 39.degree.-40.degree. C.
EXAMPLE 5
1METHYL-4-(BENZOYLOXYACETYL)PIPERAZINE HYDROCHLORIDE
A solution of 1-methylpiperazine (0.40 g, 4 mmole) in 5 ml benzene was
added dropwise while stirring to a solution of (benzoyloxy)acetylchloride
(0.80 g, 4 mmole) in 10 ml of benzene. After the addition was completed
(about 10 min) the reaction mixture was stirred at room temperature for 1
h. Ether (10 ml) was added and the mixture was filtered. The white
crystalline compound on the filter was washed with ether and finally
recrystallized from ethanol, yielding 0.70 g (59%) of the title compound.
Mp 227.degree.-228.degree. C.
EXAMPLE 6
2-BENZOYLOXY)-(N-METHYL-N-.beta.HYDROXYETHYL)ACETAMIDE
A solution of (benzoyloxy)acetyl chloride (1.5 g, 8 mmole) in 8 ml of
benzene was mixed with N-methylethanolamine (1.8 g, 24 mmole). The
solution was stirred at room temperature for 3 h and then concentrated in
vacuo. The residue was dissolved in ethyl acetate (50 ml) and water (10
ml). The layers were separated and the organic phase washed with 2M
hydrochloric acid (5 ml), water (5 ml), dried and evaporated in vacuo. The
residue crystallized by trituration with ether and standing overnight at
-20.degree. C. The compound was filtered off and recrystallized from ethyl
acetate-petroleum ether, giving 1.1 g (50%) of the title compound. Mp
78.degree.-80.degree. C.
EXAMPLE 7
2-(BENZOYLOXY)-N,N-(DICARBAMOYLMETHYL)ACETAMIDE
A solution of (benzoyloxy)acetyl chloride 0.8 g. 4 mmole) in benzene (4 ml)
was added while stirring at room temperature to a mixture of
iminodiacetamide hydrochloride (1.06 g, 6 mmole) and sodium bicarbonate
(2.52 g, 30 mmole) in water (5 ml). The mixture was stirred for 3 h. The
precipitate formed was filtered off, washed with a small amount of water
and recrystallized from water to give 0.70 g (60%) of the title compound.
Mp 195.degree.-196.degree. C.
EXAMPLE 8
N-(BENZOYLOXYMETHYLCARBONYL)PYRROLIDONE
A mixture of (benzoyloxy)acetyl chloride (1.98 g, 0.01 mole), pyrrolidone
(0.85 g, 0.01 mole) and pyridine (0.8 g, 0.01 mole) in acetone (10 ml) was
refluxed for 3 h. The cooled mixture was filtered and evaporated in vacuo.
The residue was dissolved in ethyl acetate (50 ml) and the solution washed
with a 2% aqueous solution of sodium bicarbonate, 2M hydrochloric acid and
water. After drying over anhydrous sulphate, the organic phase was
evaporated under reduced pressure to give a residue which crystallized by
addition of ether. Recrystallization from ether-petroleum ether yielded
1.6 g (65%) of the title compound. Mp 83.degree.-84.degree. C.
EXAMPLES 9-33
By following the procedures of the foregoing examples several more esters
of benzoic acid according to the invention were prepared. The structure of
these esters and their melting points are shown in Table 1.
EXAMPLE 34
2-[1-(P-CHLOROBENZOYL)-5-METHOXY-2-METHYLINDONE-3-ACETYLOXY]-N,N-DIETHYLACE
TAMIDE
Indomethacin (1.43 g, 4 mmole) and 2-chloro-N,N-diethylacetamide (0.61 g,
4.1 mmole) were dissolved in 5 ml of N,N-dimethylformamide and
triethylamine (0.56 ml, 4 mmole) and sodium iodide (60 mg) added. The
mixture was stirred at room temperature for 20 h and poured into 50 ml of
water. The mixture was extracted with ethyl acetate (2.times.50 ml). The
extract was washed with 2% aqueous solution bicarbonate and water. After
drying over anhydrous sodium sulphate the organic phase was evaporated in
vacuo. The residue was recrystallized from ethyl acetate-petroleum ether,
yielding 1.6 g (90%) of the title compound. Mp 148.degree.-149.degree. C.
TABLE 1
______________________________________
##STR9##
##STR10##
______________________________________
Example
number n R.sub.1 R.sub.2 Mp (.degree.C.)
______________________________________
9 1 CH.sub.3 C.sub.2 H.sub.5
.about.20
10 1 C.sub.2 H.sub.5
C.sub.2 H.sub.5
62.5-63.5
11 1 C.sub.3 H.sub.7
C.sub.3 H.sub.7
.about.20
12 1 iC.sub.3 H.sub.7
iC.sub.3 H.sub.7
104.5-105.5
13 1 CH.sub.2 CHCH.sub.2
CH.sub.2 CHCH.sub.2
42-43
14 1 nC.sub.4 H.sub.9
nC.sub.4 H.sub.9
.about.25
15 1 iC.sub.4 H.sub.9
iC.sub.4 H.sub.9
44-45
16 1 CH.sub.3 CH.sub.2 CH.sub.2 OH
78-80
17 1 CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH
80-82
18 1 CH.sub.3 CH.sub.2 CONH.sub.2
101-102
19 1 CH.sub.3 C.sub.6 H.sub.11
100-101
20 1 C.sub.6 H.sub.11
C.sub.6 H.sub.11
162-163
21 2 CH.sub.3 CH.sub.3 <20
22 3 CH.sub.3 CH.sub.3 40-41
23 1 C.sub.2 H.sub.5
CH.sub.2 CH.sub.2 OH
79-80
23a 1 CH.sub.3 CH.sub.2 CH.sub.2 N
158-159
(CH.sub.3).sub.2, HCl
23b 1 CH.sub.2 CH.sub.2 OCH.sub.3
CH.sub.2 CH.sub.2 OCH.sub.3
57-58
______________________________________
Example
number n R.sub.1 Mp (.degree.C.)
______________________________________
24 1
##STR11## 74-75
25 1
##STR12## 57.5-58
26 1
##STR13## 87-88
27 1
##STR14## 107-108
28 1
##STR15## 103-104
29 1
##STR16## 118-118.5
30 1
##STR17## 194-195
31 1
##STR18## 72-73
32 1
##STR19## 121-122
33 1
##STR20## 228-229
33a 1
##STR21## 54-55
______________________________________
EXAMPLE 35
2-[(+)-6-METHOXY-.alpha.-METHYL-2-NAPHTHALENEACETYLOXY]-N,N-DIETHYLACETAMID
Naproxen (1.07 g, 5 mmole) and 2-chloro-N,N-diethyl-acetamide (0.90 g, 6
mmole) were dissolved in 7 ml of N,N-dimethylformamide and triethylamine
(1.4 ml, 10 mmole) and sodium iodide (76 mg) were added. The mixture was
refluxed for 2 h, cooled and poured into 35 ml of water. The precipitate
formed after standing overnight at 4.degree. C. was collected by
filtration, washed with water and recrystalized from 95% ethanol, yielding
1.5 g (92%) of the title compound. Mp 89.degree.-89.5.degree. C.
EXAMPLE 36
2-[2-(ACETYLOXY)BENZOYLOXY]-N,N-DIETHYLACETAMIDE
To a mixture of acetylsalicylic acid (5.4 g. 0.03 mole) and
2-chloro-N,N-diethylacetamide (4.5 g, 0.03 mole) in 40 ml of ethyl acetate
was added triethylamine (4.2 ml, 0.03 mole) and sodium iodide (0.45 g,
0.003 mole). The mixture was refluxed for 4 h. After cooling the mixture
was filtered and the filtrate washed with 2M hydrochloric acid, 5% sodium
bicarbonate and water. After drying over anhydrous sodium sulphate the
solution was evaporated in vacuo leaving an oil which crystallized by
trituration with ethanol. Recrystallization from 80% ethanol afforded 6.2
g (70%) of the title compound. Mp 75.degree.-76.degree. C.
EXAMPLE 37
2-[2-HYDROXYBENZOYLOXY]-(N-METHYL-N-CARBAMOYLMETHYL)-ACETAMIDE
The ester was prepared from salicylic acid and N-chloroacetylsarcosinamide
(prepared as described in Example 87) by the procedure described in
Example 1. The crude product was recrystallized from ethyl acetate-ether.
Mp 142.degree.-143.degree. C.
EXAMPLE 38
2-(L-PHENYLALANYLOXY)-N,N-DIETHYLACETAMIDE HYDROBROMIDE
A solution of N-benzyloxycarbonyl-L-phenylalanine (3.0 g, 0.01 mole).
2-chloro-N,N-diethylacetamide (1.57 g, 0.011 mole) and triethylamine (1.4
ml, 0.01 mole) in acetonitrile (15 ml) was refluxed for 6 h. evaporated to
dryness in vacuo, and diluted with saturated aqueous sodium bicarbonate
solution. N-Benzyloxycarbonyl-L-phenylalanine N-N-diethylglycolamide ester
was collected by filtration, washed with water and recrystallized from
ethanol-water. Mp 85.5.degree.-86.5.degree. C.
This compound (2.0 g) was treated with 10 ml of 33% hydrogen bromide in
acetic acid for 1 h at room temperature. Addition of ether precipitated
the title compound, which was washed with ether and recrystallized from
methanol-ether. Mp 95.degree.-97.degree. C.
EXAMPLE 39
2-[1-(P-CHLOROBENZOYL)-5-METHOXY-2-METHYLINDOLE-3-ACETYLOXY]-N,N-DIMETHYLAC
ETAMIDE
a. To a stirred suspension of indomethacin (3.58 g, 0.01 mole) in benzene
(10 ml) at 60.degree. C. was added dropwise thionyl chloride (1.12 ml,
0.015 mole). The mixture was stirred for 1 h at 65.degree.-70.degree. C.
and concentrated to about 5 ml in vacuo. Hot petroleum ether (25 ml) was
added and the mixture filtered to give 3.2 g (85%) of
1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetyl chloride (acid
chloride of indomethacin). Mp 126.degree.-127.degree. C.
b. 2-Hydroxy-N,N-dimethylacetamide was prepared by alkaline hydrolysis of
2-(benzoyloxy)-N,N-dimethylacetamide obtained as described in Example 1.
2-(Benzoyloxy)-N,N-dimethylacetamide (20.7 g, 0.1 mole) was dissolved in
50 ml of ethanol by heating to 40.degree.-50.degree. C. Potassium
hydroxide (2M, 70 ml) was added and the mixture allowed to stand at room
temperature for 1 h. The pH of the solution was adjusted to 8.9 by
addition of 4M hydrochloric acid and the ethanol removed in vacuo. The pH
of the mixture was adjusted to 3.5-4 with hydrochloric acid. Precipitated
benzoic acid was filtered off and the filtrate was made alkaline (pH 8-9)
with potassium hydroxide. The solution was evaporated in vacuo. The
semi-solid residue obtained was slurried in ethyl acetate (100 ml) and the
mixture heated to about 60.degree. C. It was filtered, dried over sodium
sulphate and evaporated in vacuo to give crude
2-hydroxy-N,N-dimethylacetamide. This extraction process was repeated
twice. Recrystallization from ether-petroleum ether afforded 7.1 g (69%)
of the compound. Mp 49.degree.-50.degree. C.
c. Indomethacin acid chloride (1.14 g, 3 mmole) was added in portions to a
solution of 2-hydroxy-N,N-dimethylacetamide (340 mg, 3.3 mmole) in
acetonitrile (3 ml) and pyridine (320 g, 4 mmole). cooled to
0.degree.-4.degree. C. The mixture was stirred at room temperature for 4 h
and evaporated in vacuo. The residue was taken up in a mixture of water
and ethyl acetate. The organic base was separated and washed with 1M
hydrochloric acid, 5% sodium bicarbonate and water. Evaporation of the
dried solution afforded a solid residue which upon recrystallization from
ethyl acetate afforded the title compound. Mp 149.degree.-150.degree. C.
EXAMPLE 40
2-(4-AMINOBENZOYLOXY)-N,N-DIETHYLACETAMIDE
A mixture of 4-aminobenzoic acid (1.37 g. 0.01 mole),
2-chloro-N,N-diethylacetamide 2.0 ml, 0.015 mole) and
1.8-diazabicyclo[5.4.0]-undec-7-ene (1.52 g, 0.01 mole) in benzene (20 ml)
was stirred at 80.degree. C. for 4 h and then evaporated in vacuo. The
residue was taken up in ethyl acetate. After washing with 5% sodium
bicarbonate and water the ethyl acetate extract was dried and evaporated
in vacuo leaving crude title compound. Recrystallization from
ethanol-water gave 1.5 g (60%). Mp 135.degree.-136.degree. C.
EXAMPLE 41
2-[.alpha.-METHYL-4-(2-METHYLPROPYL)BENZENEACETYLOXY]-(N-METHYL-N-CARBAMOYL
METHYL)ACETAMIDE
A mixture of ibuprofen (1.03 g, 5 mmole), 2-chloroacetylsarcosinamide (0.82
g, 5 mmole), triethylamine (0.8 ml, 5.7 mmole) and sodium iodide (100 mg)
in N,N-dimethylformamide (10 ml) was stirred at room temperature for 20 h.
Water (50 ml) was added and the mixture allowed to stand at 4.degree. C.
for 5 h. The title compound precipitated was isolated by filtration,
washed with water and recrystallized from ethanol-water to give 1.35 g
(81%). Mp 100.degree.-100.5.degree. C.
EXAMPLE 42
2-[2-[(2,3-DIMETHYLPHENYL)AMINO]-BENZOYLOXY]-N,N-DIMETHYLACETAMIDE
A mixture of mefenamic acid (2.41 g, 0.01 mole),
2-chloro-N,N-dimethylacetamide (1.6 g, 0.013 mole), triethylamine (1.6 ml,
0.011 mole) and sodium iodide (0.15 g, 0.001 mole) in
N,N-dimethylformamide (10 ml) was stirred at 90.degree. C. for 2 h. Water
(50 ml) was added and the mixture allowed to stand at 4.degree. C. for 5
h. The title compound was isolated by filtration, washed with water and
recrystallized from ethanol-water (3.0 g, 92%). Mp 85.degree.-86.degree.
C.
EXAMPLE 43
2-[1-METHYL-5-(.alpha.-METHYLBENZOYL)-2H-PYRROLE-2-ACETYLOXY]-N,N-DIMETHYLA
CETAMIDE
A mixture of tolmetin (1.29 g, 5 mmole), 2-chloro-N,N-dimethylacetamide
(0.74 g, 6 mmole), triethylamine (0.84 ml, 6 mmole) and sodium iodide (50
mg) in N,N-dimethylformamide (10 ml) was stirred at 90.degree. C. for 3 h.
Water (50 ml) was added and the mixture extracted with ethyl acetate (75
ml). After washing with an aqueous bicarbonate solution and water the
extract was dried and evaporated in vacuo. The residue obtained
crystallized upon standing at -20.degree. C. and was recrystallized from
ethanol-ether to give 1.3 g (76%) of the title compound. Mp
108.degree.-109.degree. C.
EXAMPLE 44
2-[(+)-6-METHOXY-.alpha.-METHYL-2-NAPHTHALENEACETYLOXY]-N,N-(DI-.beta.-HYDR
OXYETHYL)ACETAMIDE
The compound was prepared from naproxen and
2-chloro-N,N-(di-.beta.-hydroxyethyl)acetamide by the procedure described
in Example 1. The yield was 60%. Recrystallization from ethyl acetate gave
an analytically pure product. Mp 113.degree.-114.degree. C.
EXAMPLE 45
2-[(+)-6-METHOXY-60
-METHYL-2-NAPHTHALENEACETYLOXY]-(N-METHYL-N-.beta.HYDROXYETHYL)ACETAMIDE
The compound was prepared from naproxen and 2-chloro
(N-methyl-N-.beta.hydroxyethyl)acetamide by the procedure described in
Example 1. The yield was 65%. Recrystallization from ethyl acetate gave an
analytically pure product. Mp 109.degree.-111.degree. C.
EXAMPLE 46
2-(6-PHENYLACETAMIDOPENICILLANOYLOXY)-N,N-DIETHYL-ACETAMIDE
A mixture of benzylpenicillin sodium (1.78 g, 5 mmole),
2-chloro-N,N-diethylacetamide (1.05 g, 7 mmole) and sodium iodide (75 mg)
in N-N-dimethylformamide (10 ml) was stirred at room temperature for 18 h.
Water (60 ml) was added and mixture extracted with ethyl acetate
(2.times.50 ml). The extract was washed with 5% aqueous sodium bicarbonate
and water. Evaporation of the dried organic phase in vacuo yielded a
residue which crystallized from ethanol-water. Mp 60.degree.-61.degree. C.
EXAMPLE 47
2-(BENZOYLOXY)-(N-METHYL-N-(N,N-DIMETHYLGLYCYLOXYETHYL)ACETAMIDE
(MONOFUMARATE)
A mixture of 2-(benzoyloxy)-(N-methyl-N-.beta.-hydroxyethyl)-acetamide
(0.95 g, 4 mmole), N,N-dimethylglycine (0.41 g, 4 mmole),
N,N'-dicyclohexylcarbodiimide (0.82 g, 4 mmole) and 4-toluenesulfonic acid
(50 mg) in pyridine (10 ml) was stirred at room temperature for 24 h
Methylene chloride (20 ml) was added. The mixture was filtered and the
filtrate was evaporated in vacuo. The residue was extracted with 20 ml of
boiling ethyl acetate and the extract was evaporated. The oily residue
obtained was dissolved in ether (20 ml) and a solution of fumaric acid in
2-propanol was added. After standing overnight at 4.degree. C. the title
compound was isolated by filtration in a yield of 59%. Recrystallization
from methanol-ether gave an analytically pure product. Mp
127.degree.-127.5.degree. C.
EXAMPLE 48
2-(L-4-HYDROXYPHENYLALANYLOXY)-N,N-DIETHYLACETAMIDE HYDROCHLORIDE
A mixture of N-tert-butoxycarbonyl L-tyrosine (Boc-L-tyrosine) (1.41 g, 5
mmol), 2-chloro-N,N-diethylacetamide (0.68 ml, 5 mmol), tri-ethylamine
(0.7 ml, 5 mmol) and sodium iodide (75 mg, 0.5 mmol) in
N,N-dimethylformamide (5 ml) was stirred overnight at room temperature.
Water (50 ml) was added and the mixture extracted with ethyl acetate
(2.times.50 ml). After washing with an aqueous sodium bicarbonate solution
and water the combined extracts were dried and evaporated in vacuo. The
solid residue was recrystallized from ethyl acetate to give 1.3 g of
Boc-L-tyrosine ester of 2-hydroxy-N,N-diethylacetamide, Mp
130.degree.-131.degree. C.
This ester was deprotected by stirring 0.5 g in 3 ml of 2.5M methanolic
HCl. After 1 h a clear solution was obtained. The solution was evaporated
in vacuo and the oily residue crystallized from ethanol-ether. Mp
164.degree.-166.degree. C.
EXAMPLE 49
2-(4-HYDROXYBENZOYLOXY)-N,N-DIETHYLACETAMIDE
A mixture of 4-hydroxybenzoic acid (1.38 g, 0.01 mol),
2-chloro-N,N-diethylacetamide (1.4 g, 0.01 mol) triethylamine (1.44 ml.
0.01 mol) and sodium iodide (150 mg, 0.001 mol) in N,N-dimethylformamide
(6 ml) was stirred at room temperature for 18 h. Water (100 ml) was added
and the mixture allowed to stand at 4.degree. C. for 5 h. The title
compound was isolated by filtration, washed with water and recrystallized
from ethanol-water to give 1.8 g. Mp 148.degree.-149.degree. C.
EXAMPLE 50
2-TRANS-4-(AMINOMETHYL)CYCLOHEXANOYLOXY)-N,N-DIMETHYLACETAMIDE
HYDROCHLORIDE
Tranexamic acid (3.0 g, 0.019 mol) was dissolved in 12 ml of thionyl
chloride. The solution was kept at room temperature for 30 min. Upon
addition of ether the acid chloride of tranexamic acid as hydrochloride
salt precipitated. It was filtered off and dried over P.sub.2 O.sub.5 in
vacuo, mp 138.degree.-139.degree. C.
The acid chloride (2.10 g, 0.01 mol) was added portionwise and while
stirring to a solution of 2-hydroxy-N,N-dimethylacetamide (1.24 g, 0.012
mol) in 10 ml of dioxane. The solution was stirred at 60.degree. C. for 1
h and then cooled to 0.degree.-4.degree. C. The precipitate formed was
filtered off and recrystallized from ethanol to give 1.5 g of the title
compound, mp 183.degree.-184.degree. C.
EXAMPLE 51
2-[.alpha.-METHYL-4-(2-METHYLPROPYL)BENZENEACETYLOXY]-(N-METHYL-N-(N'-MORPH
OLINOMETHYLCARBAMOYL)METHYL)ACETAMIDE HYDROCHLORIDE
2-[.alpha.-Methyl-4-(2-methylpropyl)benzeneacetyloxy]-(N-methyl-N-carbamoyl
methyl)acetamide (0.67 g, 2 mmol), prepared as described in Example 49, was
dissolved in 2.5 ml of methanol. Morpholine (0.18 g. 2 mmol) and 0.17 ml
of 37% aqueous formaldehyde solution were added The solution was heated on
a steam bath for 15 min. and evaporated in vacuo. The oily residue was
dissolved in ether (10 ml) and a 2.5M methanolic solution of HCl (1 ml)
was added followed by petroleum ether. The mixture was kept overnight at
-20.degree. C. to allow precipitation of the title compound which was
isolated by filtration, mp 154.degree.-155.degree. C.
EXAMPLES 52-86
By following the procedures of the foregoing examples several more novel
esters of the present invention were prepared. The structure of these
esters along with their melting points are shown in Table 2.
TABLE 2
__________________________________________________________________________
Compounds of Formula I wherein n = 1
Example
R--COO-- is the
number
acyloxy residue of:
R.sub.1
R.sub.2 Mp (.degree.C.)
__________________________________________________________________________
52 Naproxen CH.sub.3
CH.sub.3 150-151
53 Naproxen CH.sub.3
CH.sub.2 CONH.sub.2
179-180
54 Ibuprofen CH.sub.3
CH.sub.3 oil
55 Ketoprofen CH.sub.3
CH.sub.3 oil
56 Ketoprofen C.sub.2 H.sub.5
C.sub.2 H.sub.5
oil
57 4-Biphenylacetic
CH.sub.3
CH.sub.2 CONH.sub.2
174-175
acid
58 Flurbiprofen
CH.sub.3
CH.sub.3 74-75
59 Flurbiprofen
C.sub.2 H.sub.5
C.sub.2 H.sub.5
60-61
60 Fenbufen CH.sub.3
CH.sub.3 120-121
61 Fenbufen C.sub.2 H.sub.5
C.sub.2 H.sub.5
94-95
62 Indomethacin
C.sub.2 H.sub.5
C.sub.2 H.sub.5
104-105
63 Indomethacin
CH.sub.3
CH.sub.2 CH.sub.2 OH
138-139
64 Indomethacin
CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH
144-146
65 Tolfenamic acid
CH.sub.3
CH.sub.3 106-107
66 Tolfenamic acid
C.sub.2 H.sub.5
C.sub.2 H.sub.5
114-115
67 Tolfenamic acid
C.sub.2 H.sub.5
CH.sub.2 CH.sub.2 OH
85-86
68 Tolfenamic acid
CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH
176-180
69 Diflunisal CH.sub.3
CH.sub.3 96.5-97
70 Diflunisal C.sub.2 H.sub.5
C.sub.2 H.sub.5
75-76
71 Mephenamic acid
CH.sub.3
CH.sub.2 CH.sub.2 OH
176-180
72 L-methyldopa
C.sub.2 H.sub.5
C.sub.2 H.sub.5
122-124
73 Sulindac C.sub.2 H.sub.3
C.sub.2 H.sub.5
100-101
74 Benzylpenicillin
CH.sub.3
CH.sub.3 71-72
75 Furosemide CH.sub.3
CH.sub.3 193-194
76 Mecillinam C.sub.2 H.sub.5
C.sub.2 H.sub.5
120-122
77 Valproic acid
CH.sub.3
CH.sub.3 oil
78 Valproic acid
CH.sub.3
CH.sub.2 CONH.sub.2
57-58
79 Salicylic acid
CH.sub.3
CH.sub.3 67.5-68
80 Salicylic acid
C.sub.2 H.sub.5
C.sub.2 H.sub.5
73-74.5
81 Acetylsalicylic acid
C.sub.3 H.sub.7
C.sub.3 H.sub.7
49.5-50.5
82 Acetylsalicylic acid
iC.sub.3 H.sub.7
iC.sub.3 H.sub.7
108-109
83 Acetylsalicylic acid
CH.sub.3
CH.sub.2 COOC.sub.2 H.sub.5
47-48
84 Acetylsalicylic acid
CH.sub.3
CH.sub.2 CONH.sub.2
123-124
85 Acetylsalicylic acid
C.sub.6 H.sub.11
C.sub.6 H.sub.11
133-134
86 Acetylsalicylic acid
morpholine 97-99
__________________________________________________________________________
EXAMPLE 87
PREPARATION OF .alpha.-CHLOROACETYLSARCOSINAMIDE
Sarcosinamide hydrochloride was prepared by reacting methylamine with
2-chloroacetamide as described by Marvel et al. (1946). The compound was
recrystallized from ethanol. Mp 160.degree.-161.degree. C.
A solution of chloroacetyl chloride (0.1 mole, 11.3 g) in benzene (40 ml)
was added over 30 min to a mixture of sarcosinamide hydrochloride (0.1
mole, 12.45 g) and sodium bicarbonate (0.25 mole, 20.0 g) in 40 ml of
water. The mixture was vigorously stirred for 3 h at room temperature. The
aqueous phase was acidified with 5M hydrochloric acid to pH 5 and
extracted with ethyl acetate (3.times.400 ml). The combined extracts were
dried over anhydrous sodium sulphate and evaporated in vacuo. The solid
residue obtained was recrystallized from ethanol-ether to give 8.5 g (52%)
of the title compound. Mp 85.degree.-86.degree. C.
EXAMPLE 88
2-(ACETYLOXY)-N,N-DIMETHYLACETAMIDE
A suspension of anhydrous sodium acetate (16.4 g, 0.2 mole) and
2-chloro-N,N-dimethylacetamide (24.3 g, 0.2 mole) in toluene (70 ml) was
refluxed for 4 h. After cooling to room temperature the mixture was
filtered and the filtrate washed with water (2.times.10 ml), dried and
evaporated in vacuo. The solid residue obtained was recrystallized from
ether yielding 22.0 g (76%). Mp 52.degree.-53.degree. C.
IN-VITRO CLEAVAGE OF ESTER PRODRUGS
Reaction conditions
Solutions of various derivatives of this invention in aqueous buffer
solutions or 50-80% human plasma solutions (pH 7.4) were kept at
37.degree. C. The initial concentration of the derivatives was in the
range 3.times.10.sup.-4 -10.sup.-5 M. At various times an aliquot of the
solutions was withdrawn and analyzed by HPLC for remaining derivative as
well as for parent acid. For the plasma solutions the aliquot withdrawn
was deproteinized with methanol, ethanol or acetonitrile and after
centrifugation, the clear supernatant was injected on HPLC.
Analytical method
An HPLC method was used for the determination of the ester derivatives and
their parent acids. In this method a reversed-phase LiChrosorb RP-8 column
(250.times.4 mm) was eluted at ambient temperature with mixtures of
methanol and 0.01M acetate buffer pH 5.0, methanol and 0.01M phosphate
buffer pH 4.5 or methanol and 0.02M phosphate buffer pH 3.5. the
composition of the eluant was adjusted for each compound in order to
provide an appropriate retention time and separation of ester and the
corresponding acid. The flow-rate was 0.6-1.6 ml/min and the column
effluent was monitored spectrophotometrically at an appropriate
wavelength. Quantitation of the compounds was done by measurement of the
peak heights in relation to those of standards chromatographed under the
same conditions.
The various prodrug esters were found to be cleaved quantitatively to the
parent acids in human plasma solutions. An example is shown in FIG. 1. The
esters of the present invention hydrolyzed surprisingly rapidly in human
plasma although the rate of hydrolysis depends greatly on the substituents
R.sub.1 and R.sub.2 in Formula I. The half-lives of hydrolysis of various
derivatives in 50% human plasma solutions (pH 7.4; 37.degree. C.) are
given in Table 3. As can be seen from the data the N,N-disubstituted
2-(acyloxy)acetamide esters are particularly rapidly hydrolyzed. Thus, the
half-life for the hydrolysis of 2-(benzoyloxy)-N,N-diethylacetamide is
less than 3 sec. In pure buffer solution of the same pH (7.4) and at
37.degree. C. the half-life of hydrolysis of this compound and the related
esters listed in Table 3 was found to be greater than 1,000 h, thus
demonstrating the facile enzymatic hydrolysis at conditions similar to
those prevailing in vivo.
At initial concentrations of about 10.sup.-4 M the progress of hydrolysis
of some esters followed strict first-order kinetics (examples are shown in
FIG. 2), whereas in other cases mixed kinetics was observed. An example of
the latter is shown in FIG. 3. As seen from FIG. 3 the rate of hydrolysis
initially followed zero-order kinetics and as the substrate depleted, it
changed to follow first-order kinetics. This behaviour is typical for
enzyme-catalyzed reactions in which the initial substrate concentration is
higher than the Michaelis constant K.sub.m. At low substrate
concentrations, i.e. concentrations similar to those prevailing in vivo
for prodrug hydrolysis, the enzymatic reaction is first-order with the
half-lives referred to in Table 3.
Table 4 shows hydrolysis data for esters of various carboxylic acids
according to the present invention. The structure of the acyl moiety has
an influence on the enzymatic reactivity but in all cases a quite rapid
rate of hydrolysis in plasma was observed. By comparing the rates of
hydrolysis of the esters of the present invention with those of the
corresponding simple methyl or ethyl esters (Table 5) the much more facile
enzymatic hydrolysis of the esters disclosed herein is readily apparent.
The esters of the present invention were found to be highly stable in
acidic media. For example, no hydrolysis, i.e. (<1%), of
2-(benzoyloxy)-N,N-diethylacetamide was found to take place in 0.01M HCl
solutions kept at 37.degree. C. for 3 h.
These results show that the esters of the present invention combine a high
susceptibility to undergo enzymatic hydrolysis in plasma with a high
stability in aqueous solution, e.g. in acidic medium such as gastric
juices. In consequence, for example, the esters will remain intact in the
gastro-intestinal tract upon oral administration, the release of the free
carboxylic acid agent occurring during the absorption process or in the
blood following absorption.
WATER-SOLUBILITY AND LIPOPHILICITY OF THE ESTER PRODRUGS
The partition coefficients (P) for some esters of the present invention
were measured at 22.degree. C. using the widely-used octanol-water system.
Similarly, the solubility of the derivatives in water or aqueous buffer
solutions was determined. The values found for log P and the
water-solubilities are included in Table 3.
The results obtained show that by varying the substituents R.sub.1 and
R.sub.2 and n in Formula I it is readily feasible to obtain ester prodrug
derivatives with varying and any desirable lipophilicity or
water-solubility with retainment of a great lability to enzymatic
hydrolysis. Thus, as seen from Table 3, the derivative
2-(benzoyloxy)-N-N-(di-.beta.-hydroxyethyl)acetamide is soluble in water
to an extent of more than 70% w/v although it is a neutral compound with a
positive log P value. As a further example, the corresponding ester
derivative of naproxen (Example 44) was found to be more than 20-fold more
soluble in 0.01M HCI than parent naproxen.
BIOAVAILABILITY STUDY
The naproxen prodrug derivative described in Example 44 was administered
orally to rabbits. Similarly, naproxen itself was given orally to rabbits
in an equivalent dose (4.8 mg/kg naproxen). After drug adminstration,
blood samples were taken at various times and the plasma fraction assayed
for naproxen and prodrug using an HPLC method at the following conditions:
Column: LiChrosorb RP-8; eluent: methanol-0.02M KH.sub.2 PO.sub.4 (pH 3.5)
65:35; detection: UV at 230 nm.
As seen from Table 6 the naproxen prodrug derivative is efficiently
absorbed following oral administration. No measurable concentrations (<0.1
.mu.g/ml) of intact naproxen prodrug were observed, thus demonstrating
that the prodrug is rapidly converted back to naproxen in vivo in
accordance with the "prodrug" definition provided at the outset of this
application.
TABLE 3
______________________________________
Rates of enzymatic hydrolysis, water-solubility and partition
coefficients for various compounds of the formula
##STR22##
______________________________________
S.sup.a
log t.sub.1/2.sup.c
R.sub.1 R.sub.2 n (mg/ml)
P.sup.b
(min)
______________________________________
CH.sub.3 CH.sub.3 1 8.8 1.07 0.15
CH.sub.3 C.sub.2 H.sub.5
1 -- 1.27 0.10
C.sub.2 H.sub.5
C.sub.2 H.sub.5
1 2.0 2.06 0.04
nC.sub.3 H.sub.7
nC.sub.3 H.sub.7
1 1.1 2.65 0.14
iC.sub.3 H.sub.7
iC.sub.3 H.sub.7
1 0.12 2.56 0.08
CH.sub.2 CHCH.sub.2
CH.sub.2 CHCH.sub.2
1 0.71 2.34 0.08
nC.sub.4 H.sub.9
nC.sub.4 H.sub.9
1 0.080 3.91 3.1
iC.sub.4 H.sub.9
iC.sub.4 H.sub.9
1 0.081 3.80 <1.5
CH.sub.3 C.sub.6 H.sub.11
1 0.14 2.99 0.54
C.sub.6 H.sub.11
C.sub.6 H.sub.11
1 0.0034 -- 407
CH.sub.3 CH.sub.2 CH.sub.2 OH
1 19.3 0.58 0.20
C.sub.2 H.sub. 5
CH.sub.2 CH.sub.2 OH
1 10.8 0.93 0.16
CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH
1 720 0.17 0.42
CH.sub.3 CH.sub.2 CH.sub.2 OOC
1 >200 -- 0.08
CH.sub.2 N(CH.sub.3).sub.2.sup.d
CH.sub.3 CH.sub.2 CONH.sub.2
1 30.2 0.08 0.13
CH.sub.3 CH.sub.2 COOC.sub.2 H.sub.5
1 6.0 1.56 0.22
CH.sub.3 CH.sub.3 2 17.6 1.28 5.6
CH.sub.3 CH.sub.3 3 13.9 1.86 14.1
CH.sub.3 CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2.sup.d
1 >100 -- 0.12
CH.sub.2 CH.sub.2 OCH.sub.3
CH.sub.2 CH.sub.2 OCH.sub.3
1 -- -- 0.25
______________________________________
##STR23## n (mg/ml)S.sup.a
log P.sup.b
(min)t.sub.1/2.sup.c
______________________________________
##STR24## 1 5.4 1.20 0.83
##STR25## 1 6.3 1.44 5.7
##STR26## 1 0.78 1.95 2.5
##STR27## 1 0.75 2.30 1.0
##STR28## 1 4.2 0.90 4.9
##STR29## 1 -- -- 5.8
##STR30## 1 0.15 2.90 0.40
##STR31## 1 1.5 0.20 2.3
##STR32## 1 2.4 1.42 1.9
##STR33## 1 0.49 1.83 18
##STR34## 1 >100 -- 12.7
______________________________________
.sup.a Solubility in water at 22.degree. C.
.sup.b P is the partition coefficient between octanol and water at
22.degree. C.
.sup.c Half-life of hydrolysis in 50% human plasma (pH 7.4) at 37.degree.
C.
.sup.d Hydrochloride salt
TABLE 4
__________________________________________________________________________
Half-lives (t.sub.1/2) of hydrolysis of various compounds of the formula
##STR35##
RCOO is the
acyloxy residue of
R.sub.1
R.sub.2 t.sub.1/2 (min)
__________________________________________________________________________
Naproxen CH.sub.3
CH.sub.3 1.5
C.sub.2 H.sub.5
C.sub.2 H.sub.5
0.6
CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH
1.3
CH.sub.3
CH.sub.2 CONH.sub.2
2.5
Ibuprofen CH.sub.3
CH.sub.3 8.6
CH.sub.3
CH.sub.2 CONH.sub.2
9.6
CH.sub.3
##STR36## 10.8
Ketoprofen CH.sub.3
CH.sub.3 1.1
C.sub.2 H.sub.5
C.sub.2 H.sub.5
0.5
CH.sub.3
CH.sub.2 CONH.sub.2
2.3
Flurbiprofen
CH.sub.3
CH.sub.3 10.8
C.sub.2 H.sub.5
C.sub.2 H.sub.5
4.7
Fenbufen CH.sub.3
CH.sub.3 9.2
C.sub.2 H.sub.5
C.sub. 2 H.sub.5
3.8
Indomethacin
CH.sub.3
CH.sub.3 130
C.sub.2 H.sub.5
C.sub.2 H.sub.5
25
CH.sub.3
CH.sub.2 CH.sub.2 OH
140
CH.sub.2 CH.sub.2 OH
CH.sub.2 CH.sub.2 OH
88
Sulindac C.sub.2 H.sub.5
C.sub.2 H.sub.5
26
Tolmetin CH.sub.3
CH.sub.3 14.6
C.sub.2 H.sub.5
C.sub.2 H.sub.5
13.4
Tolfenamic acid
CH.sub.3
CH.sub.3 2.8
C.sub.2 H.sub.5
C.sub.2 H.sub.5
5.0
C.sub.2 H.sub.5
CH.sub.2 CH.sub.2 OH
3.0
4-Aminobenzoic acid
C.sub.2 H.sub.5
C.sub.2 H.sub.5
0.6
Tranexamic acid
CH.sub.3
CH.sub.3 1.2
L-Phenylalanine
C.sub.2 H.sub.5
C.sub.2 H.sub.5
0.2
L-Tyrosine C.sub.2 H.sub.5
C.sub.2 H.sub.5
0.5
4-Hydroxybenzoic acid
C.sub.2 H.sub.5
C.sub.2 H.sub.5
1.8
Salicylic acid
CH.sub.3
CH.sub.3 0.08
C.sub.2 H.sub.5
C.sub.2 H.sub.5
0.08
CH.sub.3
CH.sub.2 CONH.sub.2
0.33
##STR37## 22
Mefenamic acid
CH.sub.3
CH.sub. 3 2.4
Diflunisal C.sub.2 H.sub.5
C.sub.2 H.sub.5
79
4-Biphenylacetic acid
CH.sub.3
CH.sub.2 CONH.sub.2
2.1
__________________________________________________________________________
TABLE 5
______________________________________
Half-lives (t.sub.1/2) of hydrolysis of esters of various drugs
containing a carboxylic acid function in 80% human plasma.sup.a
t.sub.1/2
Methyl N,N-diethylglycol-
Acid ester amide ester
______________________________________
Salicylic acid 17.6 h 0.08 min
Benzoic acid 2.0 h 0.04 min
Naproxen 20.1 h.sup.b 0.6 min
Ketoprofen >20 h 0.5 min
Fenbufen 4.7 h 3.8 min
Tolmetin 19 h 13.4 min
Tolfenamic acid
100 h 5.0 min
Indomethacin 150 h 25 min
L-Phenylalanine
29 min 0.2 min
4-Hydroxybenzoic acid
>50 h 1.8 min
4-Aminobenzoic acid
>100 h.sup.b 0.6 min
Tranexamic acid
>3 h 1.2 min.sup.c
L-Tyrosine 59 min.sup.b
0.5 min
______________________________________
.sup.a At pH 7.4 and 37.degree. C.
.sup.b Value for ethyl ester
.sup.c Value for N,Ndimethylglycolamide ester
TABLE 6
______________________________________
Plasma concentrations of naproxen following oral admini-
stration of naproxen (4.8 mg/kg) or the equivalent amount of
the N,N-(.beta.-hydroxyethyl)glycolamide ester of naproxen to
rabbits.
Naproxen plasma conc.
Time after (.mu.g/ml)
administration
After naproxen
After ester
(min) administration
administration
______________________________________
10 2.8 2.7
25 5.1 5.7
50 6.4 8.3
75 7.1 8.2
100 7.4 7.7
125 7.1 6.7
200 5.4 4.0
300 3.6 3.6
400 2.7 3.3
450 2.4 3.2
______________________________________
REFERENCES CITED
Boltze, K.-H. & H. Kreisfeld (1977): Arzneim.-Forsche. 27, 1,300-1,312.
Todd, P.A. & R.C. Heel (1986): Drugs 31, 198-248.
Concilio, C. & A. Bongini (1966): Ann. Chim. (Rome) 56, 417-426.
Hankins, E.M. (1965): U.S. Pat. No. 3,173,900.
Speziale, A.J. & P.C. Hamm (1956): J. Am. Chem. Soc. 78, 2,556-2,559.
Berkelhammer, G., S. DuBreuil & R.W. Young (1961): J. Org. Chem. 26,
2,281-2,288.
Weaver, W.E. & W.M. Whaley (1947): J. Am. Chem. Soc. 69, 515-516.
Ronwin, E. (1953): J. Org. Chem. 18, 127-132.
Holysz, R.P. & H.E. Stavely (1950): J. Am. Chem. Soc. 72, 4,760-4,763.
Ferres, H. (1983): Drugs of Today 19, 499-538.
Harrison, I.T., B. Lewis, P. Nelson, W. Rooks, A. Roszkowski, A. Tomolonis
& J. Fried (1970): J. Med. Chem. 13, 203-205.
Child, R.G., A.C. Osterberg, A.E. Sloboda & A.S. Tomcufcik (1977): J.
Pharm. Sci., 66, 466-476.
Tocco, D.J., F.A. de Luna, A.E.W. Duncan, T.C. Vassil & E.H. Ulm (1982):
Drug Metab. Disp. 10, 15-19.
Larmour, I., B. Jackson, R. Cubela & C.I. Johnston (1985): Br. J. CIin.
PharmacoI. 19, 701-704.
Rakhit, A. & V. Tipnis (1984): Clin. Chem 30, 1,237-1,239.
Tipnis, V. & A. Rakhit (1985): J. Chromatogr. 345, 396-401.
Boltze, K.-H., O. Brendler, H. Jacobi, W. Opitz, S. Raddatz, P.-R. Seidel &
D. Vollbrecht (1980): Arzneim.-Forsch. 30, 1,314-1,325.
"Remington's Pharmaceutical Sciences", Sixteenth Edition (1980), Mack
Publishing Company, Easton, U.S.A.
Marvel, C.S., J.R. Elliott, F.E. Boeltner & H. Yaska (1946): J. Am. Chem.
Soc. 68, 1,681-1,686.
Top